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Study Suggests Most Autism Risk Comes from Common Genetic Variation

Autism appears to stem primarily from inherited genes common in population; each ups risk only slightly, together have big overall effect

July 20, 2014

Most genetic risk for autism comes from common inherited gene variations that can be found in many individuals without the disorder, according to a large new study. In any one individual, each of these gene variations increases autism risk only slightly.

"Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact when taken together," says senior author Joseph Buxbaum, of the Icahn School of Medicine at Mount Sinai, in New York City.

The findings suggest that autism’s development is “more like height than we thought — many small risk factors add up, each pushing a person further out on the spectrum," adds co-author Kathryn Roeder, of Carnegie Mellon University.

“This is an important paper as it represents a first attempt to estimate the role of common genetic variants in autism using a large epidemiological dataset,” comments Stephen Scherer, director of Autism Speaks Autism Ten Thousand Genomes program (AUT10K). “Their speculations may also provide ways to explain the wide range of behavioral features that we often see with autism.” Dr. Scherer was not directly involved in the new study.

The researchers analyzed genetic data from Sweden’s national public-health database. This allowed them to compare DNA variations present in nearly 3,000 individuals. They also used information from the Autism Speaks Autism Genome Project (AGP).

What determines autism risk?
Today, most experts agree that autism is typically caused by a combination of genetics and “environmental” influences. By environmental, scientists mean a range of nongenetic factors including stress, inflammation and toxic exposures during early brain development.

However, there has been little consensus on how much genes versus environment contribute to autism. Even the genetic portion of the risk has turned out to be extremely complex. For example, recent studies suggest that those with autism have many so-called de novo gene mutations. These mutations aren’t found in either parent. Rather they arise spontaneously in germ cells (sperm and eggs) or early in embryo development.

The new study attempted to measure the overall impact of common and rare inherited gene variations associated with autism. The researchers calculated that common gene variations accounted for nearly half (49 percent) of autism risk in the general population. As mentioned, these gene variations are found in many individuals who don’t have autism. No one of them appears sufficient to cause autism by itself.

The researchers calculated that another 3 percent of autism risk stemmed from rare inherited gene mutations. These include mutations that can, in and of themselves, cause autism. Examples include recently reported mutations in the CHD8 gene. Spontaneous, or de novo, mutations accounted for another 3 percent. (See figure above.)

“This important study adds strong data to a long-standing debate about the roles of common and rare genetic variants as risk factors for autism,” concludes Daniel Smith, Autism Speaks senior director for discovery science. “This study supports a role for both and should be a catalyst for the field to do studies in even larger and more diverse populations. It’s part of the reason we started the AUT10K program, and it’s the only way to better resolve the real genetic culprits and, ultimately, the best targets for safer, better medicines.”